Human respiratory syncytial virus (RSV), a member of the Paramyxovirus subfamily Pneumovirinae, is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae. It is the most common cause of viral lower respiratory tract infections in infants and children, affecting about 4 million children globally and leading to about 100,000 hospitalizations and 4,500 deaths per year in the United States alone. RSV infection is associated with recurrent episodes of bronchiolitis, bronchial obstruction and exacerbation of asthma in children. Incidence of RSV infection-induced bronchiolitis has been increasing (WO 03/028759 A1). There is no effective prophylaxis available against RSV infection. Previous attempts to develop a vaccine using a formalin-inactivated RSV vaccine not only failed but also exacerbated diseases when subsequent RSV infection occurred (Parrott et al. (1969) “respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine” Am J Epidemiol 89:422-34). Thus, development of a RSV vaccine has been a high priority at a global level.
Virus-specific cytotoxic T lymphocytes (CTL) play a major role in the clearance of RSV infection. Both antibodies and MHC-class-I restricted T lymphocytes (CTLs) mediate protections against RSV infection. The envelope proteins F and G antigens induce the majority of the neutralizing antibodies against RSV. RSV-specific CTL play a crucial role in mediating virus clearance. An analysis of the CTL repertoire in humans indicated that the N, SH, F, M, M2, and NS2 proteins are strong target antigens. In BALB/c mice, the F, N, and M2 proteins are shown to be the major target antigens of CTL activity (Domachowske et al, (1999) “Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment” Clin Microbiol Rev 12:298). Among the RSV proteins, the F protein has been found to be the major target antigen that induces anti-viral CTL.
The F protein is made of two subunits, F2 and F1. The F2 subunit dimerizes with F1 subunit to form an inactive precursor fusion protein called F0 (Rixon et al., (2002) “Multiple glycosylated forms of the respiratory syncytial virus fusion protein are expressed in virus-infected cells” J Gen Virol 83(Pt 1): 61-6). Host cell specificity of RSV infection of the epithelial cells in the respiratory tract is determined by the N-terminal region of the F2 subunit protein. Binding to the permissive cell targets is enhanced by the attachment of the G protein to glycosaminoglycans on the cell membrane of host cells (Feldman et al., (2000) “The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulfate” J Virol 74(14): 6442-7; Techaarpornkul et al. (2002) “Respiratory syncytial virus with the fusion protein as its only viral glycoprotein is less dependent on cellular glycosaminoglycans for attachment than complete virus” Virology 294(2): 296-304). Virus entry is suggested to involve the fusion of the F1 subunit with the membrane of the target cell. Zhao et al., 2000 “Structural characterization of the human respiratory syncytial virus fusion protein core” Proc Natl Acad Sci USA., 97(26):14172-7; Barghorn et al., (2000) “Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias” Biochemistry 39(38): 11714-21). The F glycoprotein has also been shown to form filamentous structures engaged in syncytium formation that further facilitate virus spread (Gower et al., (2001) “RhoA is activated during respiratory syncytial virus infection” Virology 283(2): 188-96).
Currently, passive immunization at a monthly interval with a humanized antibody to the RSV-F antigen is considered the only option available to infants, who are at a high risk for developing RSV infection. This approach is inconvenient, expensive, and only partially effective. Therefore, a previously unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with development of a safe and effective vaccine against RSV.